Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5.

OBJECTIVE: A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. METHODS: Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1α-stimulated glycosaminoglycan release in mouse femoral head cartilage explants and on interleukin-1ß-stimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. RESULTS: GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC50 ± SD: 19 ± 2 nM and <23 ± 1 nM, respectively), with 8-fold selectivity over ADAMTS4, and 60->5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 µM and 10 µM, respectively). In DMM mice, GLPG1972/S201086 (30-120 mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23-37%), cartilage structural damage (23-39%) and subchondral bone sclerosis (21-36%). In MNX rats, GLPG1972/S201086 (10-50 mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6-23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77-110%). CONCLUSIONS: GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.

Outcome of spontaneous and iatrogenic pneumothoraces managed with small-bore chest tubes.

BACKGROUND: Little is known about the efficacy of management of iatrogenic pneumothoraces with small-bore chest tubes. The aim of this study was to assess the outcome of iatrogenic pneumothoraces requiring drainage managed with a small-bore chest tube and to compare the results to spontaneous pneumothoraces treated in the same unit with the same device. The primary outcome was requirement of video-assisted thoracoscopic surgery for drainage failure; secondary outcomes were length of drainage and number of inserted chest tubes. METHODS: Patients with pneumothorax admitted between 1997 and 2007 were retrospectively identified. Traumatic pneumothoraces and those occurring under mechanical ventilation were excluded. All pneumothoraces were drained using the same small-bore chest tube (8 French) according to our local protocol. RESULTS: Five hundred sixty-one pneumothoraces were analysed, 431 (76.8%) were spontaneous pneumothoraces and 130 (23.2%) were iatrogenic. Iatrogenic pneumothoraces were associated with less requirement of video-assisted thoracoscopic surgery for drainage failure [adjusted odds ratio= 0.24 (0.04, 0.86)]. Length of drainage of iatrogenic pneumothoraces was longer than for primary spontaneous pneumothoraces (3.8 ± 3.1 vs. 2.7 ± 1.8 days, P < 0.001) and shorter than for secondary spontaneous pneumothoraces (4.6 ± 2.3 days, P = 0.004). Number of inserted chest tubes per patient was not significantly different according to pneumothoraces' aetiology. CONCLUSION: Small-bore chest tubes are feasible for treatment of iatrogenic pneumothoraces and have a better rate of success and slightly longer drainage duration than when used for spontaneous pneumothoraces.